Sodium channels anticonvulsant action

Carbamazepine exerts its anticonvulsant activity through its own action on voltage sensitive sodium channels and those of its relatively stable 10-11-epoxide. The compound shows a number of potential toxicities including skin rash, hepatic necrosis and teratogenicity. It is possible the 10-11-epoxide is the causative agent, but struc-... 

Recent drug development studies have centered on the capacity of known antiepileptic drugs (AEDs) to interact with ion channels, and it is now established that several agents appear to be exerting their effects primarily by inhibiting ion channels. Modulation of neuronal sodium channels decreases cellular excitability and the propagation of nerve impulses. Inhibition of sodium channels appears to be a major component of the mechanism of action of several anticonvulsant drugs. 

As with several other AEDs, it is difficult to ascribe a single mechanism of action to valproic acid. This compound has broad anticonvulsant activity, both in experimental studies and in the therapeutic management of human epilepsy. Valproic acid has been shown to block voltage-dependent sodium channels at therapeutically relevant concentrations. In several experimental studies, valproate caused an increase in brain GABA the mechanism was unclear. There is evidence that valproate... 

The primary action of the benzodiazepines as anticonvulsants is to enhance inhibition through their interaction with the GABAa receptor at the benzodiazepine binding site. However, there appears to be an additional action of benzodiazepines blocking voltage-dependent sodium channels. This effect is not seen at usual doses but is likely a factor in their use in the treatment of status epilepticus (discussed later). 

While its mechanism of action has not been clearly established, felbamate shows some activity as an inhibitor of voltage-dependent sodium channels in a manner similar to that of phenytoin and carbamazepine. Felbamate also interacts at the strychnine-insensitive glycine recognition site on the NMDA receptor-ionophore complex. Whether this effect is important to its anticonvulsant activity is not clear. 

Many anticonvulsant drugs, as a major part of their mechanism of action, block the sodium channel, but other effective agents do not use this mechanism. Which of the following anticonvulsants has the ability to block T-calcium currents as its primary mechanism of action ... 

Mechanism of Action An anticonvulsant whose exact mechanism is unknown. May block voltage-sensitive sodium channels, thus stabilizing neuronal membranes and regulating presynaptic transmitter release of excitatory amino acids. Therapeutic Effect Reduces seizure activity... 

Mectianism of Action An anticonvulsant that blocks sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repef if ive neuronal firing, and diminishing synapfic impulses. Therapeutic Effect Prevenfs seizures. Pharmacokinetics Complefely absorbed from GI tract and extensively metabolized in the liver to active metabolite. Protein binding 40%. Primarily excreted in urine. Half-life 2 hr metabolite, 6-10 hr. 

Mechanism of Action An anticonvulsant that blocks repetitive, sustained firing of neurons by enhancing the ability of gamma-aminobutyric acid to induce an influx of chloride ions into the neurons may also block sodium channels. Therapeutic Effect Decreases seizure activity... 

The mechanism of action of carbamazepine appears to be similar to that of phenytoin. Like phenytoin, carbamazepine shows activity against maximal electroshock seizures. Carbamazepine, like phenytoin, blocks sodium channels at therapeutic concentrations and inhibits high-frequency repetitive firing in neurons in culture (Figure 24-4). It also acts presynaptically to decrease synaptic transmission. These effects probably account for the anticonvulsant action of carbamazepine. Binding studies show that carbamazepine interacts with adenosine receptors, but the functional significance of this observation is not known. 

FIGURE 7-27. Shown here is an icon of topiramate s pharmacologic actions. By interfering with calcium channels and sodium channels, topiramate is thought both to enhance the inhibitory actions of gamma aminobutyric acid (GABA) and to reduce the excitatory actions of glutamate. Topiramate is also a carbonic anhydrase inhibitor (CAI) and as such has independent anticonvulsant actions. 

Topiramate blocks repetitive firing of cultured spinal cord neurons, as do phenytoin and carbamazepine. Its mechanism of action, therefore, is likely to involve blocking of voltage-dependent sodium channels. Topiramate also appears to potentiate the inhibitory effect of GABA, acting at a site different from the benzodiazepine or barbiturate sites. Topiramate also depresses the excitatory action of kainate on AMPA receptors. It is possible that all three of these actions contribute to topiramate s anticonvulsant effect. 

In cell culture preparations, diphenylhydantoin, carbamazepine and valproate have been shown to reduce membrane excitability at therapeutically relevant concentrations. This membrane-stabilizing effect is probably due to a block in the sodium channels. High concentrations of diazepam also have similar effects, and the membrane-stabilizing action correlates with the action of these anticonvulsants in inhibiting maximal electroshock seizures. Intracellular studies have shown that, in synaptosomes, most anticonvulsants inhibit calcium-dependent calmodulin protein kinase, an effect which would contribute to a reduction in neurotransmitter release. This action of anticonvulsants would appear to correlate with the potency of the drugs in inhibiting electroshock seizures. The result of all these disparate actions of anticonvulsants would be to diminish synaptic efficacy and thereby reduce seizure spread from an epileptic focus. 

In addition to phenytoin, carbamazepine, and lamotrigine, metabolically optimized analogs of these drugs, such as fosphenytoin and oxcarbazepine, show clinical promise. Other anticonvulsants that block sodium channels, among several mechanisms of action, include zonisamide, felbamate, topiramate, and valproate (Fig. 5). 

Phenytoin is a hydantoin derivative like dantrolene and the oldest non-sedative anticonvulsant drug known. It alters sodium, potassium and calcium conductance across cell membranes thereby altering membrane potentials and amino acid and neurotransmitter concentrations (i.e. norepinephrine (noradrenaline), acetylcholine and GABA). Its major mode of action appears to be the blockade of sodium channels and e inhibition of the generation of repetitive action potentials (membrane stabilization) (see Chs 9 and 12). 

Phenytoin possesses anticonvulsant activity without significant central nervous system (CNS) depression. At various concentrations, phenytoin has been shown to inhibit inward Na currents, outward K currents, and Ca -mediated action potentials. The ability to inhibit sodium channels is responsible for the antidysrhythmic action (class II-B) of phenytoin. Phenytoin can induce enzymes of the hepatic cytochrome P450 system. 

ANTIARRHYTHMIC agents (Class I agents, e.g. disopyramide, flecainide. lignocaine. procainamide, quinidine) are sodium-channel blockers and are mainly used to treat atrial and ventricular tachycardias (see antiarrhythmic agents). ANTIEPILEPTICS have a number of mechanisms of action, but some appear to have a component involving modulation of sodium-channel function, e.g. carbamaxepine and phenytoin (see anticonvulsants). 

Local anesthetics like lidocaine and anticonvulsants hke phenytoin do not interfere with the process of activating sodium channels itself and thus leave the action-potentialgenerating mechanism intact. However, they cause a voltage- and use-dependent block of sodium current that reduces the number of channels available for action potential... 

The possibility of other mechanisms involved in the action of PUFAs should be considered. Some studies suggest that a reduction in sodium current may also be accomplished by activation of protein kinase C (Godoy Cukierman, 1994 Linden Routtenberg, 1989), possibly by modulating the degree of phosphorylation of the sodium channel (see Catterall, 1999). As an example of the complexity of correlating mechanisms observed at the molecular and cellular levels to the in vivo anticonvulsant action. 

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